Amino nitrites, organic compounds having at least one amino group and at least one nitrile group, have been found to be useful starting materials and intermediates in the production of fine chemicals. For example, (R)-3-aminopentanenitrile is particularly useful in the synthesis of a cholesterol reducing agent. The state of the art for producing these compounds utilizes a phase transfer cyanide source or displaces the iodine of an intermediate iodo compound. Unfortunately, this methodology has proven to be infeasible on an industrial scale.
One route for the production of amino nitrites is disclosed in Caputo et al, Synthesis of Enantiopure N- and C-Protected homo-xcex2-Amino Acids by Direct Homologation of the xcex1-Amino Acids, Tetrahedron Letters, Vol. 51, No. 45, pp. 123337-12350, 1995. Caputo discloses the use of a triarylphosphine-iodine polymer bound complex in the presence of imidazole to replace the hydroxyl group with the iodo group and the subsequent displacement of the iodo group with a cyanide. The introduction of polymer bound reactants makes this methodology costly and undesirable. Moreover, Caputo utilized tetraethylammonium cyanide as a nucleophilic reagent and experienced significant deprotection of the amino group.
Another reaction scheme disclosed in Toujas, et al., Synthesis of homochiral N-Boc-xcex2-aminoaldehydes from N-Boc-xcex2-aminonitriles, Bull. Soc. Chim. Fr. (1997), 134(7), 713-717 utilizes costly solvents and results in low yields. Toujas, et al., discloses the N-Boc protection of the amino group and mesylation of the hydroxyl with methanesulfonyl chloride in the presence of triethylamine at room temperature. According to Toujas, et al., nucleophilic substitution with sodium cyanide in DMSO gives a relatively low yield of 56%.
What is needed is a reaction scheme for the production of amino nitrites from amino alcohols that is industrially feasible. Specifically what is needed is a reaction scheme that provides high yields while utilizing inexpensive reagents.
In one embodiment of the present invention a process for the preparation of chiral amino nitrile compounds from chiral amino alcohols is provided. In one aspect the process esterifies a chiral amino alcohol having an alcohol group and a protected amine group to create an electrophilic carbon having a leaving group and subsequently substitutes a cyanide for the leaving group in the presence of dimethylformamide to form a chiral amino nitrile having a protected amine group. In another aspect of the present invention the protecting group of the amine comprises t-butoxy carbonyl.
In a particularly useful embodiment the esterification of the hydroxyl is performed using a sulfonyl chloride and the leaving group comprises a sulfonate. In a preferred embodiment the esterification is performed using methyl sulfonyl chloride and the leaving group is methyl sulfonate.
In still another embodiment the cyanide used as a nucleophile is added as a salt. In a preferred embodiment sodium cyanide provided with an organic solvent is used as the nucleophile.
Another embodiment of the present invention provides for the additional step of removing the protecting group from the protected amine of the chiral amino nitrile. In one aspect of the present process the protecting group is removed by addition of an acid. In a preferred embodiment methyl sulfonic acid is used to remove the protecting group. In still another embodiment the protecting group is removed in the presence of an organic solvent.
Other objects and further benefits of the present invention will become apparent to persons having ordinary skill in the art from the following written description and accompanying figures.